SMC3

Last updated
SMC3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SMC3 , BAM, BMH, CDLS3, CSPG6, HCAP, SMC3L1, structural maintenance of chromosomes 3
External IDs OMIM: 606062 MGI: 1339795 HomoloGene: 3974 GeneCards: SMC3
Orthologs
SpeciesHumanMouse
Entrez

9126

13006

Ensembl

ENSG00000108055

ENSMUSG00000024974

UniProt

Q9UQE7

Q9CW03

RefSeq (mRNA)

NM_005445

NM_007790

RefSeq (protein)

NP_005436

NP_031816

Location (UCSC) Chr 10: 110.57 – 110.61 Mb Chr 19: 53.59 – 53.63 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. [5] SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. In humans, SMC3 is present in all cohesin complexes whereas there are multiple paralogs for the other subunits.

Contents

SMC3 is a member of the SMC protein family. Members of this family are key regulators of DNA repair, chromosome condensation and chromosome segregation.

Structure and interactions

Structure of the interface between SMC3 (blue) and SMC1 (green) (PDB 2WD5) from mice (Kurze et al., 2009) Structure of the interface between SMC3 (blue) and SMC1 (green) (PDB 2WD5) from mice (Kurze et al. 2009).png
Structure of the interface between SMC3 (blue) and SMC1 (green) (PDB 2WD5) from mice (Kurze et al., 2009)
Structure of the interface between SMC3 (blue) and RAD21 (green) (PDB 4UX3) from budding yeast (Gligoris et al., 2014) Structure of the SMC3 (blue)-RAD21 (green) interface (PDB 4UX3).png
Structure of the interface between SMC3 (blue) and RAD21 (green) (PDB 4UX3) from budding yeast (Gligoris et al., 2014)

The domain organisation of SMC proteins is evolutionarily conserved and is composed of an N-terminal Walker A motif, coiled-coil, "hinge", coiled-coil and a C-terminal Walker B motif. The protein folds back on itself to form a rod-shaped molecule with a heterodimerisation "hinge" domain at one end and an ABC-type ATPase "head" at the other. These globular domains are separated by a ~50 nm anti-parallel coiled-coil. SMC3 and SMC1 bind via their hinge domains creating V-shaped heterodimers. The N-terminal domain of RAD21 binds to the coiled coil of SMC3 just above the head domain while the C-terminal domain of RAD21 binds the head domain of SMC1. This end to end binding of the SMC3-SMC1-RAD21 trimer creates a closed ring within which DNA can be entrapped. SA1 or

When DNA is replicated and sister chromatid cohesion is established SMC3 is acetylated on a pair of highly conserved lysines by ESCO1 and ESCO2. In budding yeast this modification is sufficient to stabilise cohesin on the DNA until mitosis but in animals, binding of sororin is also required.

During meiosis, SMC3 forms cohesin complexes with SMC1ß, STAG3 and REC8 which generate cohesion between homologous chromosomes and sister chromatids. [6]

Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that presents with variable clinical abnormalities including dysmorphic features, severe growth retardation, global developmental delay, and intellectual disability. SMC3 is one of five genes that have been implicated in CdLS. [7] In one case report, a novel SMC3 gene duplication was detected in a child with failure to thrive, hypotonia and facial dysmorphic features of CdLS. [7] The same duplication was also observed in the mother, who had milder dysmorphic facies.

Mouse Model

Model organisms have been used in the study of SMC3 function. A conditional knockout mouse line, called Smc3tm1a(EUCOMM)Wtsi [15] [16] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. [17] [18] [19]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. [13] [20] Twenty two tests were carried out on mutant mice and six significant abnormalities were observed. [13] No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice. Females had a higher than normal incidence of pre-wean death in their offspring, and also had a decreased body weight. Males heterozygotes displayed a shortened, upturned snout. [13] [20]

Role in Basement Membrane

SMC3 occurs in certain cell types as a secreted protein and post-translational addition of chondroitin sulfate chains gives rise to the secreted proteoglycan bamacan, an abundant basement membrane protein. [5]

Related Research Articles

<span class="mw-page-title-main">Separase</span>

Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.

SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. SMC stands for Structural Maintenance of Chromosomes.

<span class="mw-page-title-main">Cohesin</span> Protein complex that regulates the separation of sister chromatids during cell division

Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.

<span class="mw-page-title-main">Cornelia de Lange syndrome</span> Medical condition

Cornelia de Lange syndrome (CdLS) is a genetic disorder. People with this syndrome experience a range of physical, cognitive, and medical challenges ranging from mild to severe. The syndrome has a widely varied phenotype, meaning people with the syndrome have varied features and challenges. The typical features of CdLS include thick or long eyebrows, a small nose, small stature, developmental delay, long or smooth philtrum, thin upper lip and downturned mouth.

<span class="mw-page-title-main">NIPBL</span> Protein-coding gene in the species Homo sapiens

Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a protein that in humans is encoded by the NIPBL gene. NIPBL is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex. Heterozygous mutations in NIPBL account for an estimated 60% of case of Cornelia de Lange Syndrome.

<span class="mw-page-title-main">SMC1A</span> Protein-coding gene in humans

Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the SMC1A gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells, cohesin is formed of SMC1A, SMC3, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

<span class="mw-page-title-main">RAD21</span> Protein-coding gene in humans

Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene. RAD21, an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1A, SMC3, and SCC3 [ STAG1 (SA1) and STAG2 (SA2) in multicellular organisms] proteins, involved in sister chromatid cohesion.

<span class="mw-page-title-main">DCC1</span> Protein-coding gene in the species Homo sapiens

Sister chromatid cohesion protein DCC1 is a protein that in humans is encoded by the DSCC1 gene.

<span class="mw-page-title-main">STAG2</span> Protein-coding gene in humans

Cohesin subunit SA-2 (SA2) is a protein that in humans is encoded by the STAG2 gene. SA2 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

<span class="mw-page-title-main">WAPAL</span> Protein-coding gene in the species Homo sapiens

Wings apart-like protein homolog (WAPL) is a protein that in humans is encoded by the WAPAL gene. WAPL is a key regulator of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. Cohesin has a ring-like arrangement and it is thought that it associates with the chromosome by entrapping it whether as a loop of DNA, a single strand or a pair of sister chromosomes. WAPL forms a complex with PDS5A or PDS5B and releases cohesin from DNA by opening the interface between SMC3 and RAD21.

<span class="mw-page-title-main">Shugoshin 1</span> Protein-coding gene in the species Homo sapiens

Shugoshin 1 or Shugoshin-like 1, is a protein that in humans is encoded by the SGO1 gene.

<span class="mw-page-title-main">Shugoshin 2</span> Protein-coding gene in the species Homo sapiens

Shugoshin 2(Shugoshin-2), also known as Shugoshin-like 2, is a protein which in humans is encoded by the SGO2 gene.

<span class="mw-page-title-main">PDS5B</span> Protein-coding gene in the species Homo sapiens

Sister chromatid cohesion protein PDS5 homolog B(PDS5B) is a protein that in humans is encoded by the PDS5B gene. It is a regulatory subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. The core cohesin complex is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. PDS5 associates with WAPL to stimulate the release of cohesin from DNA but during DNA replication PDS5 promotes acetylation of SMC3 by ESCO1 and ESCO2.

<span class="mw-page-title-main">REC8</span> Protein-coding gene in the species Homo sapiens

Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene.

<span class="mw-page-title-main">STAG1</span> Protein-coding gene in the species Homo sapiens

Cohesin subunit SA-1 (SA1) is a protein that in humans is encoded by the STAG1 gene. SA1 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3. There is a nonprofit community formed for those with a STAG1 Gene mutation at www.stag1gene.org.

<span class="mw-page-title-main">SMC2</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 2 (SMC-2), also known as chromosome-associated protein E (CAP-E), is a protein that in humans is encoded by the SMC2 gene. SMC2 is part of the SMC protein family and is a core subunit of condensin I and II, large protein complexes involved in chromosome condensation, overall organization. Several studies have demonstrated the necessity of SMC2 for cell division and proliferation.

<span class="mw-page-title-main">SLX4</span> Protein involved in DNA repair

SLX4 is a protein involved in DNA repair, where it has important roles in the final steps of homologous recombination. Mutations in the gene are associated with the disease Fanconi anemia.

Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.

<span class="mw-page-title-main">SMC1B</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair.SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1ß protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.

<span class="mw-page-title-main">STAG3 (gene)</span> Protein-coding gene in the species Homo sapiens

Stromal antigen 3 is a protein that in humans is encoded by the STAG3 gene. STAG3 protein is a component of a cohesin complex that regulates the separation of sister chromatids specifically during meiosis. STAG3 appears to be paramount in sister-chromatid cohesion throughout the meiotic process in human oocytes and spermatocytes.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000108055 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024974 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: SMC3 structural maintenance of chromosomes 3".
  6. ↑ Garcia-Cruz R, Brieño MA, Roig I, Grossmann M, Velilla E, Pujol A, Cabero L, Pessarrodona A, Barbero JL, Garcia Caldés M (2010). "Dynamics of cohesin proteins REC8, STAG3, SMC1 beta and SMC3 are consistent with a role in sister chromatid cohesion during meiosis in human oocytes". Hum. Reprod. 25 (9): 2316–27. doi: 10.1093/humrep/deq180 . PMID   20634189.
  7. 1 2 Infante E, Alkorta-Aranburu G, El-Gharbawy A (2017). "Rare form of autosomal dominant familial Cornelia de Lange syndrome due to a novel duplication in SMC3". Clinical Case Reports. 5 (8): 1277–1283. doi:10.1002/ccr3.1010. PMC   5538066 . PMID   28781842.
  8. ↑ "Body weight data for Smc3". Wellcome Trust Sanger Institute.
  9. ↑ "Dysmorphology data for Smc3". Wellcome Trust Sanger Institute.
  10. ↑ "DEXA data for Smc3". Wellcome Trust Sanger Institute.
  11. ↑ "Salmonella infection data for Smc3". Wellcome Trust Sanger Institute.
  12. ↑ "Citrobacter infection data for Smc3". Wellcome Trust Sanger Institute.
  13. 1 2 3 4 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID   85911512.
  14. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  15. ↑ "International Knockout Mouse Consortium".
  16. ↑ "Mouse Genome Informatics".
  17. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC   3572410 . PMID   21677750.
  18. ↑ Dolgin E (2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi: 10.1038/474262a . PMID   21677718.
  19. ↑ Collins FS, Rossant J, Wurst W (2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi: 10.1016/j.cell.2006.12.018 . PMID   17218247. S2CID   18872015.
  20. 1 2 van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC   3218837 . PMID   21722353.
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